Calibration techniques for a continuous analyte sensor

ABSTRACT

Disclosed herein are systems and methods for calibrating a continuous analyte sensor, such as a continuous glucose sensor. One such system utilizes one or more electrodes to measure an additional analyte. Such measurements may provide a baseline or sensitivity measurement for use in calibrating the sensor. Furthermore, baseline and/or sensitivity measurements may be used to trigger events such as digital filtering of data or suspending display of data.

RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.11/004,561 filed Dec. 3, 2004, which claims the benefit of U.S.Provisional Application No. 60/527,323 filed Dec. 5, 2003; U.S.Provisional Application No. 60/587,787 filed Jul. 13, 2004; and U.S.Provisional Application No. 60/614,683 filed Sep. 30, 2004. Allabove-referenced prior applications are incorporated by reference hereinin their entirety.

FIELD OF THE INVENTION

The present invention relates generally to systems and methods forprocessing analyte sensor data.

BACKGROUND OF THE INVENTION

Diabetes mellitus is a disorder in which the pancreas cannot createsufficient insulin (Type I or insulin dependent) and/or in which insulinis not effective (Type 2 or non-insulin dependent). In the diabeticstate, the victim suffers from high blood sugar, which may cause anarray of physiological derangements (for example, kidney failure, skinulcers, or bleeding into the vitreous of the eye) associated with thedeterioration of small blood vessels. A hypoglycemic reaction (low bloodsugar) may be induced by an inadvertent overdose of insulin, or after anormal dose of insulin or glucose-lowering agent accompanied byextraordinary exercise or insufficient food intake.

Conventionally, a diabetic person carries a self-monitoring bloodglucose (SMBG) monitor, which typically comprises uncomfortable fingerpricking methods. Due to the lack of comfort and convenience, a diabeticwill normally only measure his or her glucose level two to four timesper day. Unfortunately, these time intervals are so far spread apartthat the diabetic will likely find out too late, sometimes incurringdangerous side effects, of a hyper- or hypo-glycemic condition. In fact,it is not only unlikely that a diabetic will take a timely SMBG value,but the diabetic will not know if their blood glucose value is going up(higher) or down (lower) based on conventional methods, inhibiting theirability to make educated insulin therapy decisions.

SUMMARY OF THE INVENTION

A variety of continuous glucose sensors have been developed fordetecting and/or quantifying glucose concentration in a host. Thesesensors have typically required one or more blood glucose measurements,or the like, from which to calibrate the continuous glucose sensor tocalculate the relationship between the current output of the sensor andblood glucose measurements, to provide meaningful values to a patient ordoctor. Unfortunately, continuous glucose sensors are conventionallyalso sensitive to non-glucose related changes in the baseline currentand sensitivity over time, for example, due to changes in a host'smetabolism, maturation of the tissue at the biointerface of the sensor,interfering species which cause a measurable increase or decrease in thesignal, or the like. Therefore, in addition to initial calibration,continuous glucose sensors should be responsive to baseline and/orsensitivity changes over time, which requires recalibration of thesensor. Consequently, users of continuous glucose sensors have typicallybeen required to obtain numerous blood glucose measurements daily and/orweekly in order to maintain calibration of the sensor over time.

The preferred embodiments provide improved calibration techniques thatutilize electrode systems and signal processing that providesmeasurements useful in simplifying and updating calibration that allowsthe patient increased convenience (for example, by requiring fewerreference glucose values) and confidence (for example, by increasingaccuracy of the device).

One aspect of the present invention is a method for measuring asensitivity change of a glucose sensor implanted in a host over a timeperiod comprising: 1) measuring a first signal in the host by obtainingat least one glucose-related sensor data point, wherein the first signalis measured at a glucose-measuring electrode disposed beneath anenzymatic portion of a membrane system on the sensor; 2) measuring asecond signal in the host by obtaining at least one non-glucose constantdata point, wherein the second signal is measured beneath the membranesystem on the sensor; and 3) monitoring the second signal over a timeperiod, whereby a sensitivity change associated with solute transportthrough the membrane system is measured. In one embodiment, the secondsignal is indicative of a presence or absence of a water-solubleanalyte. The water-soluble analyte may comprise urea. In one embodiment,the second signal is measured at an oxygen-measuring electrode disposedbeneath a non-enzymatic portion of the membrane system. In oneembodiment, the glucose-measuring electrode incrementally measuresoxygen, whereby the second signal is measured. In one embodiment, thesecond signal is measured at an oxygen sensor disposed beneath themembrane system. In one embodiment, the sensitivity change is calculatedas a glucose-to-oxygen ratio, whereby an oxygen threshold is determinedthat is indicative of a stability of the glucose sensor. One embodimentfurther comprises filtering the first signal responsive to the stabilityof the glucose sensor. One embodiment further comprises displaying aglucose value derived from the first signal, wherein the display issuspended depending on the stability of the glucose sensor. Oneembodiment further comprises calibrating the first signal, wherein thecalibrating step is suspended when the glucose sensor is determined tobe stable. One embodiment further comprises calibrating the glucosesensor when the sensitivity change exceeds a preselected value. The stepof calibrating may comprise receiving a reference signal from areference analyte monitor, the reference signal comprising at least onereference data point. The step of calibrating may comprise using thesensitivity change to calibrate the glucose sensor. The step ofcalibrating may be performed repeatedly at a frequency responsive to thesensitivity change. One embodiment further comprises determining astability of glucose transport through the membrane system, wherein thestability of glucose transport is determined by measuring thesensitivity change over a time period. One embodiment further comprisesa step of prohibiting calibration of the glucose sensor when glucosetransport is determined to be unstable. One embodiment further comprisesa step of filtering at least one glucose-related sensor data point whenglucose transport is determined to be unstable.

Another aspect of the present invention is a system for measuringglucose in a host, comprising a glucose-measuring electrode configuredto generate a first signal comprising at least one glucose-relatedsensor data point, wherein the glucose-measuring electrode is disposedbeneath an enzymatic portion of a membrane system on a glucose sensorand a transport-measuring electrode configured to generate a secondsignal comprising at least one non-glucose constant analyte data point,wherein the transport-measuring electrode is situated beneath themembrane system on the glucose sensor. One embodiment further comprisesa processor module configured to monitor the second signal whereby asensitivity change associated with transport of the non-glucose constantanalyte through the membrane system over a time period is measured. Inone embodiment, the transport-measuring electrode is configured tomeasure oxygen. In one embodiment, the processor module is configured todetermine whether a glucose-to-oxygen ratio exceeds a threshold level,wherein a value is calculated from the first signal and the secondsignal, wherein the value is indicative of the glucose-to-oxygen ratio.In one embodiment, the processor module is configured to calibrate theglucose-related sensor data point in response to the sensitivity change.In one embodiment, the processor module is configured to receivereference data from a reference analyte monitor, the reference datacomprising at least one reference data point, wherein the processormodule is configured to use the reference data point for calibrating theglucose-related sensor data point. In one embodiment, the processormodule is configured to use the sensitivity change for calibrating theglucose-related sensor data point. In one embodiment, the processormodule is configured to calibrate the glucose-related sensor data pointrepeatedly at a frequency, wherein the frequency is selected based onthe sensitivity change. One embodiment further comprises a stabilitymodule configured to determine a stability of glucose transport throughthe membrane system, wherein the stability of glucose transport iscorrelated with the sensitivity change. In one embodiment, the processormodule is configured to prohibit calibration of the glucose-relatedsensor data point when the stability of glucose transport falls below athreshold. In one embodiment, the processor module is configured toinitiate filtering of the glucose-related sensor data point when thestability of glucose transport falls below a threshold.

Another aspect of the present invention is a method for processing datafrom a glucose sensor in a host, comprising: 1) measuring a first signalassociated with glucose and non-glucose related electroactive compounds,wherein the first signal is measured at a first electrode disposedbeneath an active enzymatic portion of a membrane system; 2) measuring asecond signal associated with a non-glucose related electroactivecompound, wherein the second signal is measured at a second electrodethat is disposed beneath a non-enzymatic portion of the membrane system;and 3) monitoring the second signal over a time period, whereby a changein the non-glucose related electroactive compound in the host ismeasured. One embodiment further comprises a step of subtracting thesecond signal from the first signal, whereby a differential signalcomprising at least one glucose sensor data point is determined. Thestep of subtracting may be performed electronically in the sensor.Alternatively, the step of subtracting may be performed digitally in thesensor or an associated receiver. One embodiment further comprisescalibrating the glucose sensor, wherein the step of calibratingcomprises: 1) receiving reference data from a reference analyte monitor,the reference data comprising at least two reference data points; 2)providing at least two matched data pairs by matching the reference datato substantially time corresponding sensor data; and 3) calibrating theglucose sensor using the two or more matched data pairs and thedifferential signal. One embodiment further comprises a step ofcalibrating the glucose sensor in response to a change in thenon-glucose related electroactive compound over the time period. Thestep of calibrating may comprise receiving reference data from areference analyte monitor, the reference data comprising at least onereference data point. The step of calibrating may comprise using thechange in the non-glucose related electroactive compound over the timeperiod to calibrate the glucose sensor. The step of calibrating may beperformed repeatedly at a frequency, wherein the frequency is selectedbased on the change in the non-glucose related electroactive compoundover the time period. One embodiment further comprises prohibitingcalibration of the glucose sensor when the change in the non-glucoserelated electroactive compound rises above a threshold during the timeperiod. One embodiment further comprises filtering the glucose sensordata point when the change in the non-glucose related electroactivecompound rises above a threshold during the time period. One embodimentfurther comprises measuring a third signal in the host by obtaining atleast one non-glucose constant data point, wherein the third signal ismeasured beneath the membrane system. One embodiment further comprisesmonitoring the third signal over a time period, whereby a sensitivitychange associated with solute transport through the membrane system ismeasured. In one embodiment, an oxygen-measuring electrode disposedbeneath the non-enzymatic portion of the membrane system measures thethird signal. In one embodiment, the first electrode measures the thirdsignal by incrementally measuring oxygen. In one embodiment, an oxygensensor disposed beneath the membrane system measures the third signal.One embodiment further comprises determining whether a glucose-to-oxygenratio exceeds a threshold level by calculating a value from the firstsignal and the second signal, wherein the value is indicative of theglucose-to-oxygen ratio. One embodiment further comprises calibratingthe glucose sensor in response to the sensitivity change measured over atime period. The step of calibrating may comprise receiving referencedata from a reference analyte monitor, the reference data comprising atleast one reference data point. The step of calibrating may compriseusing the sensitivity change. The step of calibrating may be performedrepeatedly at a frequency, wherein the frequency is selected based onthe sensitivity change. One embodiment further comprises determining aglucose transport stability through the membrane system, wherein theglucose transport stability corresponds to the sensitivity change over aperiod of time. One embodiment further comprises prohibiting calibrationof the glucose sensor when the glucose transport stability falls below athreshold. One embodiment further comprises filtering theglucose-related sensor data point when the glucose transport stabilityfalls below a threshold.

Still another aspect of the present invention is a system for measuringglucose in a host, comprising a first working electrode configured togenerate a first signal associated with a glucose related electroactivecompound and a non-glucose related electroactive compound, wherein thefirst electrode is disposed beneath an active enzymatic portion of amembrane system on a glucose sensor; a second working electrodeconfigured to generate a second signal associated with the non-glucoserelated electroactive compound, wherein the second electrode is disposedbeneath a non-enzymatic portion of the membrane system on the glucosesensor; and a processor module configured to monitor the second signalover a time period, whereby a change in the non-glucose relatedelectroactive compound is measured. One embodiment further comprises asubtraction module configured to subtract the second signal from thefirst signal, whereby a differential signal comprising at least oneglucose sensor data point is determined. The subtraction module maycomprise a differential amplifier configured to electronically subtractthe second signal from the first signal. The subtraction module maycomprise at least one of hardware and software configured to digitallysubtract the second signal from the first signal. One embodiment furthercomprises a reference electrode, wherein the first working electrode andthe second working electrode are operatively associated with thereference electrode. One embodiment further comprises a counterelectrode, wherein the first working electrode and the second workingelectrode are operatively associated with the counter electrode. Oneembodiment further comprises a first reference electrode and a secondreference electrode, wherein the first reference electrode isoperatively associated with the first working electrode, and wherein thesecond reference electrode is operatively associated with the secondworking electrode. One embodiment further comprises a first counterelectrode and a second counter electrode, wherein the first counterelectrode is operatively associated with the first working electrode,and wherein the second counter electrode is operatively associated withthe second working electrode. One embodiment further comprises areference input module adapted to obtain reference data from a referenceanalyte monitor, the reference data comprising at least one referencedata point, wherein the processor module is configured to format atleast one matched data pair by matching the reference data tosubstantially time corresponding glucose sensor data and subsequentlycalibrating the system using at least two matched data pairs and thedifferential signal. In one embodiment, the processor module isconfigured to calibrate the system in response to the change in thenon-glucose related electroactive compound in the host over the timeperiod. In one embodiment, the processor module is configured to requestreference data from a reference analyte monitor, the reference datacomprising at least one reference data point, wherein the processormodule is configured to recalibrate the system using the reference data.In one embodiment, the processor module is configured to recalibrate thesystem using the change in the non-glucose related electroactivecompound measured over the time period. In one embodiment, the processormodule is configured to repeatedly recalibrate at a frequency, whereinthe frequency is selected based on the change in the non-glucose relatedelectroactive compound over the time period. In one embodiment, theprocessor module is configured to prohibit calibration of the systemwhen a change in the non-glucose related electroactive compound risesabove a threshold during the time period. In one embodiment, theprocessor module is configured to filter the glucose sensor data pointwhen the change in the non-glucose related electroactive compound risesabove a threshold during the time period. One embodiment furthercomprises a third electrode configured to generate a third signal, thethird signal comprising at least one non-glucose constant analyte datapoint, wherein the third electrode is disposed beneath the membranesystem on the sensor. The third electrode may be configured to measureoxygen. In one embodiment, the processor module is configured todetermine whether a glucose-to-oxygen ratio exceeds a threshold level,wherein a value indicative of the glucose-to-oxygen ratio is calculatedfrom the first signal and the second signal. In one embodiment, theprocessor module is configured to monitor the third signal over a timeperiod, whereby a sensitivity change associated with solute transportthrough the membrane system is measured. In one embodiment, theprocessor module is configured to calibrate the glucose-related sensordata point in response to the sensitivity change. In one embodiment, theprocessor module is configured to receive reference data from areference analyte monitor, the reference data comprising at least onereference data point, wherein the processor module is configured tocalibrate the glucose sensor data point using the reference data point.In one embodiment, the processor module is configured to calibrate theglucose-related sensor data point repeatedly at a frequency, wherein thefrequency is selected based on the sensitivity change. One embodimentfurther comprises a stability module configured to determine a stabilityof glucose transport through the membrane system, wherein the stabilityof glucose transport is correlated with the sensitivity change. In oneembodiment, the processor module is configured to prohibit calibrationof the glucose-related sensor data point when the stability of glucosetransport falls below a threshold. In one embodiment, the processormodule is configured to filter the glucose-related sensor data pointwhen the stability of glucose transport falls below a threshold.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is a perspective view of a continuous analyte sensor, includingan implantable body with a membrane system disposed thereon

FIG. 1B is an expanded view of an alternative embodiment of a continuousanalyte sensor, illustrating the in vivo portion of the sensor.

FIG. 2A is a schematic view of a membrane system in one embodiment,configured for deposition over the electroactive surfaces of the analytesensor of FIG. 1A.

FIG. 2B is a schematic view of a membrane system in an alternativeembodiment, configured for deposition over the electroactive surfaces ofthe analyte sensor of FIG. 1B.

FIG. 3A which is a cross-sectional exploded schematic view of a sensingregion of a continuous glucose sensor in one embodiment wherein anactive enzyme of an enzyme domain is positioned only over theglucose-measuring working electrode.

FIG. 3B is a cross-sectional exploded schematic view of a sensing regionof a continuous glucose sensor in another embodiment, wherein an activeportion of the enzyme within the enzyme domain positioned over theauxiliary working electrode has been deactivated.

FIG. 4 is a block diagram that illustrates continuous glucose sensorelectronics in one embodiment.

FIG. 5 is a drawing of a receiver for the continuous glucose sensor inone embodiment.

FIG. 6 is a block diagram of the receiver electronics in one embodiment.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

The following description and examples illustrate some exemplaryembodiments of the disclosed invention in detail. Those of skill in theart will recognize that there are numerous variations and modificationsof this invention that are encompassed by its scope. Accordingly, thedescription of a certain exemplary embodiment should not be deemed tolimit the scope of the present invention.

DEFINITIONS

In order to facilitate an understanding of the disclosed invention, anumber of terms are defined below.

The term “analyte,” as used herein, is a broad term and is used in itsordinary sense, including, but not limited to, to refer to a substanceor chemical constituent in a biological fluid (for example, blood,interstitial fluid, cerebral spinal fluid, lymph fluid or urine) thatcan be analyzed. Analytes may include naturally occurring substances,artificial substances, metabolites, and/or reaction products. In someembodiments, the analyte for measurement by the sensor heads, devices,and methods disclosed herein is glucose. However, other analytes arecontemplated as well, including but not limited to acarboxyprothrombin;acylcarnitine; adenine phosphoribosyl transferase; adenosine deaminase;albumin; alpha-fetoprotein; amino acid profiles (arginine (Krebs cycle),histidine/urocanic acid, homocysteine, phenylalanine/tyrosine,tryptophan); andrenostenedione; antipyrine; arabinitol enantiomers;arginase; benzoylecgonine (cocaine); biotinidase; biopterin; c-reactiveprotein; carnitine; carnosinase; CD4; ceruloplasmin; chenodeoxycholicacid; chloroquine; cholesterol; cholinesterase; conjugated 1-βhydroxy-cholic acid; cortisol; creatine kinase; creatine kinase MMisoenzyme; cyclosporin A; d-penicillamine; de-ethylchloroquine;dehydroepiandrosterone sulfate; DNA (acetylator polymorphism, alcoholdehydrogenase, alpha 1-antitrypsin, cystic fibrosis, Duchenne/Beckermuscular dystrophy, analyte-6-phosphate dehydrogenase,hemoglobinopathies, A, S, C, E, D-Punjab, beta-thalassemia, hepatitis Bvirus, HCMV, HIV-1, HTLV-1, Leber hereditary optic neuropathy, MCAD,RNA, PKU, Plasmodium vivax, sexual differentiation, 21-deoxycortisol);desbutylhalofantrine; dihydropteridine reductase; diptheria/tetanusantitoxin; erythrocyte arginase; erythrocyte protoporphyrin; esterase D;fatty acids/acylglycines; free β-human chorionic gonadotropin; freeerythrocyte porphyrin; free thyroxine (FT4); free tri-iodothyronine(FT3); fumarylacetoacetase; galactose/gal-1-phosphate;galactose-1-phosphate uridyltransferase; gentamicin; analyte-6-phosphatedehydrogenase; glutathione; glutathione peroxidase; glycocholic acid;glycosylated hemoglobin; halofantrine; hemoglobin variants;hexosaminidase A; human erythrocyte carbonic anhydrase I; 17alpha-hydroxyprogesterone; hypoxanthine phosphoribosyl transferase;immunoreactive trypsin; lactate; lead; lipoproteins ((a), B/A-1, β);lysozyme; mefloquine; netilmicin; phenobarbitone; phenytoin;phytanic/pristanic acid; progesterone; prolactin; prolidase; purinenucleoside phosphorylase; quinine; reverse tri-iodothyronine (rT3);selenium; serum pancreatic lipase; sissomicin; somatomedin C; specificantibodies (adenovirus, anti-nuclear antibody, anti-zeta antibody,arbovirus, Aujeszky's disease virus, dengue virus, Dracunculusmedinensis, Echinococcus granulosus, Entamoeba histolytica, enterovirus,Giardia duodenalisa, Helicobacter pylori, hepatitis B virus, herpesvirus, HIV-1, IgE (atopic disease), influenza virus, Leishmaniadonovani, leptospira, measles/mumps/rubella, Mycobacterium leprae,Mycoplasma pneumoniae, Myoglobin, Onchocerca volvulus, parainfluenzavirus, Plasmodium falciparum, poliovirus, Pseudomonas aeruginosa,respiratory syncytial virus, rickettsia (scrub typhus), Schistosomamansoni, Toxoplasma gondii, Trepenoma pallidium, Trypanosomacruzi/rangeli, vesicular stomatis virus, Wuchereria bancrofti, yellowfever virus); specific antigens (hepatitis B virus, HIV-1);succinylacetone; sulfadoxine; theophylline; thyrotropin (TSH); thyroxine(T4); thyroxine-binding globulin; trace elements; transferrin;UDP-galactose-4-epimerase; urea; uroporphyrinogen I synthase; vitamin A;white blood cells; and zinc protoporphyrin. Salts, sugar, protein, fat,vitamins and hormones naturally occurring in blood or interstitialfluids may also constitute analytes in certain embodiments. The analytemay be naturally present in the biological fluid, for example, ametabolic product, a hormone, an antigen, an antibody, and the like.Alternatively, the analyte may be introduced into the body, for example,a contrast agent for imaging, a radioisotope, a chemical agent, afluorocarbon-based synthetic blood, or a drug or pharmaceuticalcomposition, including but not limited to insulin; ethanol; cannabis(marijuana, tetrahydrocannabinol, hashish); inhalants (nitrous oxide,amyl nitrite, butyl nitrite, chlorohydrocarbons, hydrocarbons); cocaine(crack cocaine); stimulants (amphetamines, methamphetamines, Ritalin,Cylert, Preludin, Didrex, PreState, Voranil, Sandrex, Plegine);depressants (barbituates, methaqualone, tranquilizers such as Valium,Librium, Miltown, Serax, Equanil, Tranxene); hallucinogens(phencyclidine, lysergic acid, mescaline, peyote, psilocybin); narcotics(heroin, codeine, morphine, opium, meperidine, Percocet, Percodan,Tussionex, Fentanyl, Darvon, Talwin, Lomotil); designer drugs (analogsof fentanyl, meperidine, amphetamines, methamphetamines, andphencyclidine, for example, Ecstasy); anabolic steroids; and nicotine.The metabolic products of drugs and pharmaceutical compositions are alsocontemplated analytes. Analytes such as neurochemicals and otherchemicals generated within the body may also be analyzed, such as, forexample, ascorbic acid, uric acid, dopamine, noradrenaline,3-methoxytyramine (3MT), 3,4-Dihydroxyphenylacetic acid (DOPAC),Homovanillic acid (HVA), 5-Hydroxytryptamine (5HT), and5-Hydroxyindoleacetic acid (FHIAA).

The term “continuous glucose sensor,” as used herein, is a broad termand is used in its ordinary sense, including, but not limited to, adevice that continuously or continually measures glucose concentration,for example, at time intervals ranging from fractions of a second up to,for example, 1, 2, or 5 minutes, or longer. It should be understood thatcontinuous glucose sensors can continually measure glucose concentrationwithout requiring user initiation and/or interaction for eachmeasurement, such as described with reference to U.S. Pat. No.6,001,067, for example.

The phrase “continuous glucose sensing,” as used herein, is a broad termand is used in its ordinary sense, including, but not limited to, theperiod in which monitoring of plasma glucose concentration iscontinuously or continually performed, for example, at time intervalsranging from fractions of a second up to, for example, 1, 2, or 5minutes, or longer.

The term “biological sample,” as used herein, is a broad term and isused in its ordinary sense, including, but not limited to, sample of ahost body, for example, blood, interstitial fluid, spinal fluid, saliva,urine, tears, sweat, or the like.

The term “host,” as used herein, is a broad term and is used in itsordinary sense, including, but not limited to, mammals such as humans.

The term “biointerface membrane,” as used herein, is a broad term and isused in its ordinary sense, including, but not limited to, a permeableor semi-permeable membrane that can include two or more domains and istypically constructed of materials of a few microns thickness or more,which can be placed over the sensing region to keep host cells (forexample, macrophages) from gaining proximity to, and thereby damagingthe membrane system or forming a barrier cell layer and interfering withthe transport of glucose across the tissue-device interface.

The term “membrane system,” as used herein, is a broad term and is usedin its ordinary sense, including, but not limited to, a permeable orsemi-permeable membrane that can be comprised of two or more domains andis typically constructed of materials of a few microns thickness ormore, which may be permeable to oxygen and are optionally permeable toglucose. In one example, the membrane system comprises an immobilizedglucose oxidase enzyme, which enables an electrochemical reaction tooccur to measure a concentration of glucose.

The term “domain,” as used herein is a broad term and is used in itsordinary sense, including, but not limited to, regions of a membranethat can be layers, uniform or non-uniform gradients (for example,anisotropic), functional aspects of a material, or provided as portionsof the membrane.

The term “copolymer,” as used herein, is a broad term and is used in itsordinary sense, including, but not limited to, polymers having two ormore different repeat units and includes copolymers, terpolymers,tetrapolymers, or the like.

The term “sensing region,” as used herein, is a broad term and is usedin its ordinary sense, including, but not limited to, the region of amonitoring device responsible for the detection of a particular analyte.In one embodiment, the sensing region generally comprises anon-conductive body, at least one electrode, a reference electrode and aoptionally a counter electrode passing through and secured within thebody forming an electrochemically reactive surface at one location onthe body and an electronic connection at another location on the body,and a membrane system affixed to the body and covering theelectrochemically reactive surface.

The term “electrochemically reactive surface,” as used herein, is abroad term and is used in its ordinary sense, including, but not limitedto, the surface of an electrode where an electrochemical reaction takesplace. In one embodiment, a working electrode measures hydrogen peroxidecreating a measurable electronic current.

The term “electrochemical cell,” as used herein, is a broad term and isused in its ordinary sense, including, but not limited to, a device inwhich chemical energy is converted to electrical energy. Such a celltypically consists of two or more electrodes held apart from each otherand in contact with an electrolyte solution. Connection of theelectrodes to a source of direct electric current renders one of themnegatively charged and the other positively charged. Positive ions inthe electrolyte migrate to the negative electrode (cathode) and therecombine with one or more electrons, losing part or all of their chargeand becoming new ions having lower charge or neutral atoms or molecules;at the same time, negative ions migrate to the positive electrode(anode) and transfer one or more electrons to it, also becoming new ionsor neutral particles. The overall effect of the two processes is thetransfer of electrons from the negative ions to the positive ions, achemical reaction.

The term “enzyme” as used herein, is a broad term and is used in itsordinary sense, including, but not limited to, a protein orprotein-based molecule that speeds up a chemical reaction occurring in aliving thing. Enzymes may act as catalysts for a single reaction,converting a reactant (also called an analyte herein) into a specificproduct. In one exemplary embodiment of a glucose oxidase-based glucosesensor, an enzyme, glucose oxidase (GOX) is provided to react withglucose (the analyte) and oxygen to form hydrogen peroxide.

The term “co-analyte” as used herein, is a broad term and is used in itsordinary sense, including, but not limited to, a molecule required in anenzymatic reaction to react with the analyte and the enzyme to form thespecific product being measured. In one exemplary embodiment of aglucose sensor, an enzyme, glucose oxidase (GOX) is provided to reactwith glucose and oxygen (the co-analyte) to form hydrogen peroxide.

The term “constant analyte” as used herein, is a broad term and is usedin its ordinary sense, including, but not limited to, an analyte thatremains relatively constant over a time period, for example over an hourto a day as compared to other variable analytes. For example, in aperson with diabetes, oxygen and urea may be relatively constantanalytes in particular tissue compartments relative to glucose, which isknown to oscillate between about 40 and 400 mg/dL during a 24-hourcycle. Although analytes such as oxygen and urea are known to oscillateto a lesser degree, for example due to physiological processes in ahost, they are substantially constant, relative to glucose, and can bedigitally filtered, for example low pass filtered, to minimize oreliminate any relatively low amplitude oscillations. Constant analytesother than oxygen and urea are also contemplated.

The term “proximal” as used herein, is a broad term and is used in itsordinary sense, including, but not limited to, near to a point ofreference such as an origin or a point of attachment. For example, insome embodiments of a membrane system that covers an electrochemicallyreactive surface, the electrolyte domain is located more proximal to theelectrochemically reactive surface than the resistance domain.

The term “distal” as used herein, is a broad term and is used in itsordinary sense, including, but not limited to, spaced relatively farfrom a point of reference, such as an origin or a point of attachment.For example, in some embodiments of a membrane system that covers anelectrochemically reactive surface, a resistance domain is located moredistal to the electrochemically reactive surfaces than the electrolytedomain.

The term “substantially” as used herein, is a broad term and is used inits ordinary sense, including, but not limited to, being largely but notnecessarily wholly that which is specified.

The term “computer,” as used herein, is broad term and is used in itsordinary sense, including, but not limited to, machine that can beprogrammed to manipulate data.

The term “modem,” as used herein, is a broad term and is used in itsordinary sense, including, but not limited to, an electronic device forconverting between serial data from a computer and an audio signalsuitable for transmission over a telecommunications connection toanother modem.

The terms “processor module” and “microprocessor,” as used herein, arebroad terms and are used in their ordinary sense, including, but notlimited to, a computer system, state machine, processor, or the likedesigned to perform arithmetic and logic operations using logiccircuitry that responds to and processes the basic instructions thatdrive a computer.

The term “ROM,” as used herein, is a broad term and is used in itsordinary sense, including, but not limited to, read-only memory, whichis a type of data storage device manufactured with fixed contents. ROMis broad enough to include EEPROM, for example, which is electricallyerasable programmable read-only memory (ROM).

The term “RAM,” as used herein, is a broad term and is used in itsordinary sense, including, but not limited to, a data storage device forwhich the order of access to different locations does not affect thespeed of access. RAM is broad enough to include SRAM, for example, whichis static random access memory that retains data bits in its memory aslong as power is being supplied.

The term “A/D Converter,” as used herein, is a broad term and is used inits ordinary sense, including, but not limited to, hardware and/orsoftware that converts analog electrical signals into correspondingdigital signals.

The term “RF transceiver,” as used herein, is a broad term and is usedin its ordinary sense, including, but not limited to, a radio frequencytransmitter and/or receiver for transmitting and/or receiving signals.

The terms “raw data stream” and “data stream,” as used herein, are broadterms and are used in their ordinary sense, including, but not limitedto, an analog or digital signal directly related to the analyteconcentration measured by the analyte sensor. In one example, the rawdata stream is digital data in “counts” converted by an A/D converterfrom an analog signal (for example, voltage or amps) representative ofan analyte concentration. The terms broadly encompass a plurality oftime spaced data points from a substantially continuous analyte sensor,which comprises individual measurements taken at time intervals rangingfrom fractions of a second up to, for example, 1, 2, or 5 minutes orlonger.

The term “counts,” as used herein, is a broad term and is used in itsordinary sense, including, but not limited to, a unit of measurement ofa digital signal. In one example, a raw data stream measured in countsis directly related to a voltage (for example, converted by an A/Dconverter), which is directly related to current from a workingelectrode.

The term “electronic circuitry,” as used herein, is a broad term and isused in its ordinary sense, including, but not limited to, thecomponents (for example, hardware and/or software) of a deviceconfigured to process data. In the case of an analyte sensor, the dataincludes biological information obtained by a sensor regarding theconcentration of the analyte in a biological fluid. U.S. Pat. Nos.4,757,022, 5,497,772 and 4,787,398, which are hereby incorporated byreference in their entirety, describe suitable electronic circuits thatcan be utilized with devices of certain embodiments.

The term “potentiostat,” as used herein, is a broad term and is used inits ordinary sense, including, but not limited to, an electrical systemthat applies a potential between the working and reference electrodes ofa two- or three-electrode cell at a preset value and measures thecurrent flow through the working electrode. The potentiostat forceswhatever current is necessary to flow between the working and counterelectrodes to keep the desired potential, as long as the needed cellvoltage and current do not exceed the compliance limits of thepotentiostat.

The terms “operably connected” and “operably linked,” as used herein,are broad terms and are used in their ordinary sense, including, but notlimited to, one or more components being linked to another component(s)in a manner that allows transmission of signals between the components.For example, one or more electrodes can be used to detect the amount ofglucose in a sample and convert that information into a signal; thesignal can then be transmitted to an electronic circuit. In this case,the electrode is “operably linked” to the electronic circuit. Theseterms are broad enough to include wired and wireless connectivity.

The term “smoothing” and “filtering,” as used herein, are broad termsand are used in their ordinary sense, including, but not limited to,modification of a set of data to make it smoother and more continuousand remove or diminish outlying points, for example, by performing amoving average of the raw data stream.

The term “algorithm,” as used herein, is a broad term and is used in itsordinary sense, including, but not limited to, the computationalprocesses (for example, programs) involved in transforming informationfrom one state to another, for example using computer processing.

The term “regression,” as used herein, is a broad term and is used inits ordinary sense, including, but not limited to, finding a line inwhich a set of data has a minimal measurement (for example, deviation)from that line. Regression can be linear, non-linear, first order,second order, and so forth. One example of regression is least squaresregression.

The term “pulsed amperometric detection,” as used herein, is a broadterm and is used in its ordinary sense, including, but not limited to,an electrochemical flow cell and a controller, which applies thepotentials and monitors current generated by the electrochemicalreactions. The cell can include one or multiple working electrodes atdifferent applied potentials. Multiple electrodes can be arranged sothat they face the chromatographic flow independently (parallelconfiguration), or sequentially (series configuration).

The term “calibration,” as used herein, is a broad term and is used inits ordinary sense, including, but not limited to, the process ofdetermining the relationship between the sensor data and correspondingreference data, which may be used to convert sensor data into meaningfulvalues substantially equivalent to the reference. In some embodiments,namely in continuous analyte sensors, calibration may be updated orrecalibrated over time as changes in the relationship between the sensorand reference data occur, for example due to changes in sensitivity,baseline, transport, metabolism, or the like.

The term “sensor analyte values” and “sensor data,” as used herein, arebroad terms and are used in their ordinary sense, including, but notlimited to, data received from a continuous analyte sensor, includingone or more time-spaced sensor data points.

The term “reference analyte values” and “reference data,” as usedherein, are broad terms and are used in their ordinary sense, including,but not limited to, data from a reference analyte monitor, such as ablood glucose meter, or the like, including one or more reference datapoints. In some embodiments, the reference glucose values are obtainedfrom a self-monitored blood glucose (SMBG) test (for example, from afinger or forearm blood test) or a YSI (Yellow Springs Instruments)test, for example.

The term “matched data pairs,” as used herein, is a broad term and isused in its ordinary sense, including, but not limited to, referencedata (for example, one or more reference analyte data points) matchedwith substantially time corresponding sensor data (for example, one ormore sensor data points).

The terms “interferants” and “interfering species,” as used herein, arebroad terms and are used in their ordinary sense, including, but notlimited to, effects and/or species that interfere with the measurementof an analyte of interest in a sensor to produce a signal that does notaccurately represent the analyte measurement. In one example of anelectrochemical sensor, interfering species are compounds with anoxidation potential that overlaps with the analyte to be measured,producing a false positive signal.

Overview

The preferred embodiments provide a continuous analyte sensor thatmeasures a concentration of the analyte of interest or a substanceindicative of the concentration or presence of the analyte. In someembodiments, the analyte sensor is an invasive, minimally invasive, ornon-invasive device, for example a subcutaneous, transdermal, orintravascular device. In some embodiments, the analyte sensor mayanalyze a plurality of intermittent biological samples. The analytesensor may use any method of analyte-measurement, including enzymatic,chemical, physical, electrochemical, spectrophotometric, polarimetric,calorimetric, radiometric, or the like.

In general, analyte sensors provide at least one working electrode andat least one reference electrode, which are configured to measure asignal associated with a concentration of the analyte in the host, suchas described in more detail below, and as appreciated by one skilled inthe art. The output signal is typically a raw data stream that is usedto provide a useful value of the measured analyte concentration in ahost to the patient or doctor, for example. However, the analyte sensorsof the preferred embodiments may further measure at least one additionalsignal associated with the baseline and/or sensitivity of the analytesensor, thereby enabling monitoring of baseline and/or sensitivitychanges that may occur in a continuous analyte sensor over time.

In general, continuous analyte sensors define a relationship betweensensor-generated measurements (for example, current in nA or digitalcounts after A/D conversion) and a reference measurement (for example,mg/dL or mmol/L) that are meaningful to a user (for example, patient ordoctor). In the case of an implantable enzyme-based electrochemicalglucose sensors, the sensing mechanism generally depends on phenomenathat are linear with glucose concentration, for example: (1) diffusionof glucose through a membrane system (for example, biointerface membraneand membrane system) situated between implantation site and theelectrode surface, (2) an enzymatic reaction within the membrane system(for example, membrane system), and (3) diffusion of the H₂O₂ to thesensor. Because of this linearity, calibration of the sensor can beunderstood by solving an equation:

y=mx+b

where y represents the sensor signal (counts), x represents theestimated glucose concentration (mg/dL), m represents the sensorsensitivity to glucose (counts/mg/dL), and b represents the baselinesignal (counts). Because both sensitivity m and baseline b change overtime in vivo, calibration has conventionally required at least twoindependent, matched data pairs (x₁, y₁; x₂, y₂) to solve for m and band thus allow glucose estimation when only the sensor signal, y isavailable. Matched data pairs can be created by matching reference data(for example, one or more reference glucose data points from a bloodglucose meter, or the like) with substantially time corresponding sensordata (for example, one or more glucose sensor data points) to provideone or more matched data pairs, such as described in co-pending U.S.patent application Ser. No. 10/633,367, which is incorporated herein byreference in its entirety.

Accordingly, in some embodiments, the sensing region is configured tomeasure changes in sensitivity of the analyte sensor over time, whichcan be used to trigger calibration, update calibration, avoid inaccuratecalibration (for example, calibration during unstable periods), and/ortrigger filtering of the sensor data. Namely, the analyte sensor isconfigured to measure a signal associated with a non-analyte constant inthe host. Preferably, the non-analyte constant signal is measuredbeneath the membrane system on the sensor. In one example of a glucosesensor, a non-glucose constant that can be measured is oxygen, wherein ameasured change in oxygen transport is indicative of a change in thesensitivity of the glucose signal, which can be measured by switchingthe bias potential of the working electrode, an auxiliaryoxygen-measuring electrode, an oxygen sensor, or the like, as describedin more detail elsewhere herein.

Alternatively or additionally, in some embodiments, the sensing regionis configured to measure changes in the amount of background noise(baseline) in the signal, which can be used to trigger calibration,update calibration, avoid inaccurate calibration (for example,calibration during unstable periods), and/or trigger filtering of thesensor data. In one example of a glucose sensor, the baseline iscomposed substantially of signal contribution due to factors other thanglucose (for example, interfering species, non-reaction-related hydrogenperoxide, or other electroactive species with an oxidation potentialthat overlaps with hydrogen peroxide). Namely, the glucose sensor isconfigured to measure a signal associated with the baseline (allnon-glucose related current generated) measured by sensor in the host.In some embodiments, an auxiliary electrode located beneath anon-enzymatic portion of the membrane system is used to measure thebaseline signal. In some embodiments, the baseline signal is subtractedfrom the glucose signal (which includes the baseline) to obtain thesignal contribution substantially only due to glucose. Subtraction maybe accomplished electronically in the sensor using a differentialamplifier, digitally in the receiver, and/or otherwise in the hardwareor software of the sensor or receiver as is appreciated by one skilledin the art, and as described in more detail elsewhere herein.

One skilled in the art appreciates that the above-described sensitivityand baseline signal measurements can be combined to benefit from bothmeasurements in a single analyte sensor.

Exemplary Continuous Glucose Sensor Configurations

Although two exemplary glucose sensor configurations are described indetail below, it should be understood that the systems and methodsdescribed herein can be applied to any device capable of continually orcontinuously detecting a concentration of analyte of interest andproviding an output signal that represents the concentration of thatanalyte, for example oxygen, lactose, hormones, cholesterol,medicaments, viruses, or the like.

FIG. 1A is a perspective view of an analyte sensor, including animplantable body with a sensing region including a membrane systemdisposed thereon. In the illustrated embodiment, the analyte sensor 10 aincludes a body 12 and a sensing region 14 including membrane andelectrode systems configured to measure the analyte. In this embodiment,the sensor 10 a is preferably wholly implanted into the subcutaneoustissue of a host, such as described in co-pending. U.S. patentapplication Ser. No. 10/885,476 filed Jul. 6, 2004 and entitled “SYSTEMSAND METHODS FOR MANUFACTURE OF AN ANALYTE SENSOR INCLUDING A MEMBRANESYSTEM”; co-pending U.S. patent application Ser. No. 10/838,912 filedMay 3, 2004 and entitled, “IMPLANTABLE ANALYTE SENSOR”; U.S. patentapplication Ser. No. 10/789,359 filed Feb. 26, 2004 and entitled,“INTEGRATED DELIVERY DEVICE FOR A CONTINUOUS GLUCOSE SENSOR”; U.S.application Ser. No. 10/646,333 filed Aug. 22, 2003 entitled, “OPTIMIZEDSENSOR GEOMETRY FOR AN IMPLANTABLE GLUCOSE SENSOR”; U.S. applicationSer. No. 10/633,367 filed Aug. 1, 2003 entitled, “SYSTEM AND METHODS FORPROCESSING ANALYTE SENSOR DATA”; and U.S. Pat. No. 6,001,067 issued Dec.14, 1999 and entitled “DEVICE AND METHOD FOR DETERMINING ANALYTELEVELS”, each of which are incorporated herein by reference in theirentirety

The body 12 of the sensor 10 a can be formed from a variety ofmaterials, including metals, ceramics, plastics, or composites thereof.In one embodiment, the sensor is formed from thermoset molded around thesensor electronics. Co-pending U.S. patent application Ser. No.10/646,333, entitled, “OPTIMIZED DEVICE GEOMETRY FOR AN IMPLANTABLEGLUCOSE DEVICE” discloses suitable configurations for the body, and isincorporated by reference in its entirety.

In some embodiments, the sensing region 14 includes a glucose-measuringworking electrode 16, an optional auxiliary working electrode 18, areference electrode 20, and a counter electrode 22. Generally, thesensing region 14 includes means to measure two different signals, 1) afirst signal associated with glucose and non-glucose relatedelectroactive compounds having a first oxidation potential, wherein thefirst signal is measured at the glucose-measuring working electrodedisposed beneath an active enzymatic portion of a membrane system, and2) a second signal associated with the baseline and/or sensitivity ofthe glucose sensor. In some embodiments, wherein the second signalmeasures sensitivity, the signal is associated with at least onenon-glucose constant data point, for example, wherein the auxiliaryworking electrode 18 is configured to measure oxygen. In someembodiments, wherein the second signal measures baseline, the signal isassociated with at non-glucose related electroactive compounds havingthe first oxidation potential, wherein the second signal is measured atan auxiliary working electrode 18 and is disposed beneath anon-enzymatic portion of the membrane system, such as described in moredetail elsewhere herein.

Preferably, a membrane system (see FIG. 2A) is deposited over theelectroactive surfaces of the sensor 10 a and includes a plurality ofdomains or layers, such as described in more detail below, withreference to FIGS. 2A and 2B. In general, the membrane system may bedisposed over (deposited on) the electroactive surfaces using methodsappreciated by one skilled in the art. See co-pending U.S. patentapplication Ser. No. 10/885,476, filed Jul. 6, 2004 and entitled“SYSTEMS AND METHODS FOR MANUFACTURE OF AN ANALYTE SENSOR INCLUDING AMEMBRANE SYSTEM,” which is incorporated herein by reference in itsentirety.

The sensing region 14 comprises electroactive surfaces, which are incontact with an electrolyte phase (not shown), which is a free-flowingfluid phase disposed between the membrane system 22 and theelectroactive surfaces. In this embodiment, the counter electrode isprovided to balance the current generated by the species being measuredat the working electrode. In the case of glucose oxidase based analytesensors, the species being measured at the working electrode is H₂O₂.Glucose oxidase catalyzes the conversion of oxygen and glucose tohydrogen peroxide and gluconate according to the following reaction:

Glucose+O₂→Gluconate+H₂O₂

The change in H₂O₂ can be monitored to determine glucose concentrationbecause for each glucose molecule metabolized, there is a proportionalchange in the product H₂O₂. Oxidation of H₂O₂ by the working electrodeis balanced by reduction of ambient oxygen, enzyme generated H₂O₂, orother reducible species at the counter electrode. The H₂O₂ produced fromthe glucose oxidase reaction further reacts at the surface of theworking electrode and produces two protons (2H⁺), two electrons (2e⁻),and one oxygen molecule (O₂). Preferably, one or more potentiostat isemployed to monitor the electrochemical reaction at the electroactivesurface of the working electrode(s). The potentiostat applies a constantpotential to the working electrode and its associated referenceelectrode to determine the current produced at the working electrode.The current that is produced at the working electrode (and flows throughthe circuitry to the counter electrode) is substantially proportional tothe amount of H₂O₂ that diffuses to the working electrodes. The outputsignal is typically a raw data stream that is used to provide a usefulvalue of the measured analyte concentration in a host to the patient ordoctor, for example.

FIG. 1B is an expanded view of an alternative exemplary embodiment of acontinuous analyte sensor 10 b, also referred to as a transcutaneousanalyte sensor, particularly illustrating the in vivo portion of thesensor. In this embodiment, the in vivo portion of the sensor 10 b isthe portion adapted for insertion under the host's skin, while an exvivo portion of the sensor (not shown) is the portion that remains abovethe host's skin after sensor insertion and operably connects to anelectronics unit. In the illustrated embodiment, the analyte sensor 10b, includes three electrodes: a glucose-measuring working electrode 16,an optional auxiliary working electrode 18, and at least one additionalelectrode 20, which may function as a counter and/or referenceelectrode, hereinafter referred to as the reference electrode 20.Generally, the sensor 10 b may include the ability to measure twodifferent signals, 1) a first signal associated with glucose andnon-glucose related electroactive compounds having a first oxidationpotential, wherein the first signal is measured at the glucose-measuringworking electrode disposed beneath an active enzymatic portion of amembrane system, and 2) a second signal associated with the baselineand/or sensitivity of the glucose sensor, such as described in moredetail above with reference to FIG. 1A.

Preferably, each electrode is formed from a fine wire, with a diameterin the range of 0.001 to 0.010 inches, for example, and may be formedfrom plated wire or bulk material, however the electrodes may bedeposited on a substrate or other known configurations as is appreciatedby one skilled in the art.

In one embodiment, the glucose-measuring working electrode 16 comprisesa wire formed from a conductive material, such as platinum, palladium,graphite, gold, carbon, conductive polymer, or the like. Theglucose-measuring working electrode 16 is configured and arranged tomeasure the concentration of glucose. The glucose-measuring workingelectrode 16 is covered with an insulating material, for example anon-conductive polymer. Dip-coating, spray-coating, or other coating ordeposition techniques can be used to deposit the insulating material onthe working electrode, for example. In one preferred embodiment, theinsulating material comprises Parylene, which can be an advantageousconformal coating for its strength, lubricity, and electrical insulationproperties, however, a variety of other insulating materials can beused, for example, fluorinated polymers, polyethyleneterephthalate,polyurethane, polyimide, or the like.

In this embodiment, the auxiliary working electrode 18 comprises a wireformed from a conductive material, such as described with reference tothe glucose-measuring working electrode 16 above. Preferably, thereference electrode 20, which may function as a reference electrodealone, or as a dual reference and counter electrode, is formed fromsilver, Silver/Silver chloride, or the like.

Preferably, the electrodes are juxtapositioned and/or twisted with oraround each other, however other configurations are also possible. Inone example, the auxiliary working electrode 18 and reference electrode20 may be helically wound around the glucose-measuring working electrode16 as illustrated in FIG. 1B. Alternatively, the auxiliary workingelectrode 18 and reference electrode 20 may be formed as a double helixaround a length of the glucose-measuring working electrode 16 (notshown). The assembly of wires may then be optionally coated togetherwith an insulating material, similar to that described above, in orderto provide an insulating attachment. Some portion of the coated assemblystructure is then stripped, for example using an excimer laser, chemicaletching, or the like, to expose the necessary electroactive surfaces. Insome alternative embodiments, additional electrodes may be includedwithin the assembly, for example, a three-electrode system (includingseparate reference and counter electrodes) as is appreciated by oneskilled in the art.

Preferably, a membrane system (see FIG. 2B) is deposited over theelectroactive surfaces of the sensor 10 b and includes a plurality ofdomains or layers, such as described in more detail below, withreference to FIGS. 2A and 2B. The membrane system may be deposited onthe exposed electroactive surfaces using known thin film techniques (forexample, spraying, electro-depositing, dipping, or the like). In oneexemplary embodiment, each domain is deposited by dipping the sensorinto a solution and drawing out the sensor at a speed that provides theappropriate domain thickness. In general, the membrane system may bedisposed over (deposited on) the electroactive surfaces using methodsappreciated by one skilled in the art.

In the illustrated embodiment, the sensor is an enzyme-basedelectrochemical sensor, wherein the glucose-measuring working electrode16 measures the hydrogen peroxide produced by the enzyme catalyzedreaction of glucose being detected and creates a measurable electroniccurrent (for example, detection of glucose utilizing glucose oxidaseproduces H₂O₂ peroxide as a by product, H₂O₂ reacts with the surface ofthe working electrode producing two protons (2H⁺), two electrons (2e⁻)and one molecule of oxygen (O₂) which produces the electronic currentbeing detected), such as described in more detail above and as isappreciated by one skilled in the art. Preferably, one or morepotentiostat is employed to monitor the electrochemical reaction at theelectroactive surface of the working electrode(s). The potentiostatapplies a constant potential to the working electrode and its associatedreference electrode to determine the current produced at the workingelectrode. The current that is produced at the working electrode (andflows through the circuitry to the counter electrode) is substantiallyproportional to the amount of H₂O₂ that diffuses to the workingelectrodes. The output signal is typically a raw data stream that isused to provide a useful value of the measured analyte concentration ina host to the patient or doctor, for example.

Some alternative analyte sensors that can benefit from the systems andmethods of the preferred embodiments include U.S. Pat. No. 5,711,861 toWard et al., U.S. Pat. No. 6,642,015 to Vachon et al., U.S. Pat. No.6,654,625 to Say et al., U.S. Pat. No. 6,565,509 to Say et al., U.S.Pat. No. 6,514,718 to Heller, U.S. Pat. No. 6,465,066 to Essenpreis etal., U.S. Pat. No. 6,214,185 to Offenbacher et al., U.S. Pat. No.5,310,469 to Cunningham et al., and U.S. Pat. No. 5,683,562 to Shafferet al., U.S. Pat. No. 6,579,690 to Bonnecaze et al., U.S. Pat. No.6,484,046 to Say et al., U.S. Pat. No. 6,512,939 to Colvin et al., U.S.Pat. No. 6,424,847 to Mastrototaro et al., U.S. Pat. No. 6,424,847 toMastrototaro et al, for example. All of the above patents areincorporated in their entirety herein by reference and are not inclusiveof all applicable analyte sensors; in general, it should be understoodthat the disclosed embodiments are applicable to a variety of analytesensor configurations.

Membrane System

In general, analyte sensors include a membrane system that functions tocontrol the flux of a biological fluid therethrough and/or to protectsensitive regions of the sensor from contamination by the biologicalfluid, for example. Some conventional electrochemical enzyme-basedanalyte sensors generally include a membrane system that controls theflux of the analyte being measured, protects the electrodes fromcontamination of the biological fluid, and/or provides an enzyme thatcatalyzes the reaction of the analyte with a co-factor, for example.See, e.g., co-pending U.S. patent application Ser. No. 10/838,912, filedMay 3, 2004 entitled “IMPLANTABLE ANALYTE SENSOR,” which is incorporatedherein by reference in its entirety.

The membrane system 22 can include any membrane configuration suitablefor use with any analyte sensor (such as described with reference toFIGS. 1A and 1B). In the illustrated embodiments, the membrane system 22includes a plurality of domains, all or some of which can be adhered tothe analyte sensor 10 as is appreciated by one skilled in the art. Inone embodiment, the membrane system generally provides one or more ofthe following functions: 1) protection of the exposed electrode surfacefrom the biological environment, 2) diffusion resistance (limitation) ofthe analyte, 3) a catalyst for enabling an enzymatic reaction, 4)limitation or blocking of interfering species, and 5) hydrophilicity atthe electrochemically reactive surfaces of the sensor interface, such asdescribed in co-pending U.S. patent application Ser. No. 10/838,912,filed May 3, 2004 and entitled “IMPLANTABLE ANALYTE SENSOR,” which isincorporated herein by reference in its entirety. Accordingly, themembrane system 22 preferably includes a plurality of domains or layers,for example, resistance domain 30, an interference domain 28, an enzymedomain 26 (for example, glucose oxidase), an electrolyte domain 24, andmay additionally include a cell disruptive domain, a cell impermeabledomain, and/or an oxygen domain (not shown), such as described in moredetail in the above-cited U.S. patent application Ser. No. 10/838,912.However, it is understood that a membrane system modified for othersensors, for example, by including fewer or additional domains is withinthe scope of the preferred embodiments.

In some embodiments, the domains of the biointerface and membranesystems are formed from materials such as silicone,polytetrafluoroethylene, polyethylene-co-tetrafluoroethylene,polyolefin, polyester, polycarbonate, biostable polytetrafluoroethylene,homopolymers, copolymers, terpolymers of polyurethanes, polypropylene(PP), polyvinylchloride (PVC), polyvinylidene fluoride (PVDF),polybutylene terephthalate (PBT), polymethylmethacrylate (PMMA),polyether ether ketone (PEEK), polyurethanes, cellulosic polymers,polysulfones and block copolymers thereof including, for example,di-block, tri-block, alternating, random and graft copolymers.Co-pending U.S. patent application Ser. No. 10/838,912, which isincorporated herein by reference in its entirety, describes biointerfaceand membrane system configurations and materials that may be applied tothe preferred embodiments.

FIGS. 2A and 2B are schematic views membrane systems in some embodimentsthat may be disposed over the electroactive surfaces of an analytesensors of FIGS. 1A and 1B, respectively, wherein the membrane systemincludes one or more of the following domains: a resistance domain 30,an enzyme domain 28, an interference domain 26, and an electrolytedomain 24, such as described in more detail below. However, it isunderstood that the membrane system 22 can be modified for use in othersensors, by including only one or more of the domains, additionaldomains not recited above, or for other sensor configurations. Forexample, the interference domain can be removed when other methods forremoving interferants are utilized, such as an auxiliary electrode formeasuring and subtracting out signal due to interferants. As anotherexample, an “oxygen antenna domain” composed of a material that hashigher oxygen solubility than aqueous media so that it concentratesoxygen from the biological fluid surrounding the biointerface membranecan be added. The oxygen antenna domain can then act as an oxygen sourceduring times of minimal oxygen availability and has the capacity toprovide on demand a higher rate of oxygen delivery to facilitate oxygentransport to the membrane. This enhances function in the enzyme reactiondomain and at the counter electrode surface when glucose conversion tohydrogen peroxide in the enzyme domain consumes oxygen from thesurrounding domains. Thus, this ability of the oxygen antenna domain toapply a higher flux of oxygen to critical domains when needed improvesoverall sensor function.

Electrolyte Domain

In some preferred embodiments, an electrolyte domain 24 is provided toensure an electrochemical reaction occurs at the electroactive surfaces.Preferably, the electrolyte domain includes a semipermeable coating thatmaintains hydrophilicity at the electrochemically reactive surfaces ofthe sensor interface. The electrolyte domain enhances the stability ofthe interference domain 26 by protecting and supporting the materialthat makes up the interference domain. The electrolyte domain alsoassists in stabilizing the operation of the sensor by overcomingelectrode start-up problems and drifting problems caused by inadequateelectrolyte. The buffered electrolyte solution contained in theelectrolyte domain also protects against pH-mediated damage that canresult from the formation of a large pH gradient between thesubstantially hydrophobic interference domain and the electrodes due tothe electrochemical activity of the electrodes. In one embodiment, theelectrolyte domain 24 includes a flexible, water-swellable,substantially solid gel-like film.

Interference Domain

Interferants are molecules or other species that are electro-reduced orelectro-oxidized at the electrochemically reactive surfaces, eitherdirectly or via an electron transfer agent, to produce a false signal.In one embodiment, the interference domain 26 prevents the penetrationof one or more interferants (for example, urate, ascorbate, oracetaminophen) into the electrolyte phase around the electrochemicallyreactive surfaces. Preferably, this type of interference domain is muchless permeable to one or more of the interferants than to the analyte.

In one embodiment, the interference domain 26 can include ioniccomponents incorporated into a polymeric matrix to reduce thepermeability of the interference domain to ionic interferants having thesame charge as the ionic components. In another embodiment, theinterference domain 26 includes a catalyst (for example, peroxidase) forcatalyzing a reaction that removes interferants. U.S. Pat. No. 6,413,396and U.S. Pat. No. 6,565,509 disclose methods and materials foreliminating interfering species. However, in the preferred embodimentsany suitable method or material can be employed.

In one embodiment, the interference domain 26 includes a thin membranethat is designed to limit diffusion of species, e.g., those greater than34 g/mol in molecular weight, for example. The interference domainpermits analytes and other substances (for example, hydrogen peroxide)that are to be measured by the electrodes to pass through, whilepreventing passage of other substances, such as potentially interferingsubstances. In one embodiment, the interference domain 26 is constructedof polyurethane.

Enzyme Domain

In the preferred embodiments, the enzyme domain 28 provides a catalystto catalyze the reaction of the analyte and its co-reactant, asdescribed in greater detail above. In preferred embodiments, the enzymedomain includes glucose oxidase. However other oxidases, for example,galactose oxidase or uricase, can be used.

For example, enzyme-based electrochemical analyte sensor performance atleast partially depends on a response that is neither limited by enzymeactivity nor cofactor concentration. Because enzymes, including glucoseoxidase, are subject to deactivation as a function of ambientconditions, this behavior needs to be accounted for in constructinganalyte sensors. Preferably, the domain is constructed of aqueousdispersions of colloidal polyurethane polymers including the enzyme.However, some alternative embodiments construct the enzyme domain froman oxygen antenna material, for example, silicone or fluorocarbons, inorder to provide a supply of excess oxygen during transient ischemia.Preferably, the enzyme is immobilized within the domain, as isappreciated by one skilled in the art.

Resistance Domain

The resistance domain 30 includes a semipermeable membrane that controlsthe flux of analytes of interest (for example, glucose and oxygen) tothe underlying enzyme domain 28. As a result, the upper limit oflinearity of an analyte measurement can be extended to a much highervalue than what can be achieved without the resistance domain. In oneembodiment of a glucose sensor, the resistance domain 38 exhibits anoxygen-to-glucose permeability ratio of approximately 200:1. As aresult, one-dimensional reactant diffusion is adequate to provide excessoxygen at all reasonable glucose and oxygen concentrations found in thesubcutaneous matrix (See Rhodes et al., Anal. Chem., 66:1520-1529(1994)).

In some alternative embodiments, a lower ratio of oxygen-to-glucose canbe sufficient to provide excess oxygen by using an oxygen antenna domain(for example, a silicone or fluorocarbon based material or domain) toenhance the supply/transport of oxygen to the enzyme domain. In otherwords, if more oxygen is supplied to the enzyme, then more glucose canalso be supplied to the enzyme without the rate of this reaction beinglimited by a lack of glucose. In some alternative embodiments, theresistance domain is formed from a silicone composition, such asdescribed in copending U.S. application Ser. No. 10/685,636 filed Oct.28, 2003, and entitled, “SILICONE COMPOSITION FOR BIOCOMPATIBLEMEMBRANE,” which is incorporated herein by reference in its entirety.

In one preferred embodiment, the resistance layer includes a homogenouspolyurethane membrane with both hydrophilic and hydrophobic regions tocontrol the diffusion of glucose and oxygen to an analyte sensor, themembrane being fabricated easily and reproducibly from commerciallyavailable materials. In preferred embodiments, the thickness of theresistance domain is from about 10 microns or less to about 200 micronsor more.

The above-described domains are exemplary and are not meant to belimiting to the following description, for example, their systems andmethods are designed for the exemplary enzyme-based electrochemicalsensor embodiment.

Membrane Configurations

FIGS. 3A to 3B are cross-sectional exploded schematic views of thesensing region of a glucose sensor 10, which show architectures of themembrane system 22 disposed over electroactive surfaces of glucosesensors in some embodiments. In the illustrated embodiments of FIGS. 3Aand 3B, the membrane system 22 is positioned at least over theglucose-measuring working electrode 16 and the optional auxiliaryworking electrode 18, however the membrane system may be positioned overthe reference and/or counter electrodes 20,22 in some embodiments.

Reference is now made to FIG. 3A, which is a cross-sectional explodedschematic view of the sensing region in one embodiment wherein an activeenzyme 32 of the enzyme domain is positioned only over theglucose-measuring working electrode 16. In this embodiment, the membranesystem is formed such that the glucose oxidase 32 only exists above theglucose-measuring working electrode 16. In one embodiment, during thepreparation of the membrane system 22, the enzyme domain coatingsolution can be applied as a circular region similar to the diameter ofthe glucose-measuring working electrode 16. This fabrication can beaccomplished in a variety of ways such as screen-printing or padprinting. Preferably, the enzyme domain is pad printed during the enzymedomain fabrication with equipment as available from Pad Print Machineryof Vermont (Manchester, Vt.). This embodiment provides the active enzyme32 above the glucose-measuring working electrode 16 only, so that theglucose-measuring working electrode 16 (and not the auxiliary workingelectrode 18) measures glucose concentration. Additionally, thisembodiment provides an added advantage of eliminating the consumption ofO₂ above the counter electrode (if applicable) by the oxidation ofglucose with glucose oxidase.

FIG. 3B is a cross-sectional exploded schematic view of a sensing regionof the preferred embodiments, and wherein the portion of the activeenzyme within the membrane system 22 positioned over the auxiliaryworking electrode 18 has been deactivated 34. In one alternativeembodiment, the enzyme of the membrane system 22 may be deactivated 34everywhere except for the area covering the glucose-measuring workingelectrode 16 or may be selectively deactivated only over certain areas(for example, auxiliary working electrode 18, counter electrode 22,and/or reference electrode 20) by irradiation, or the like. In such acase, a mask (for example, such as those used for photolithography) canbe placed above the membrane that covers the glucose-measuring workingelectrode 16. In this way, exposure of the masked membrane toultraviolet light deactivates the glucose oxidase in all regions exceptthat covered by the mask.

In some alternative embodiments, the membrane system is disposed on thesurface of the electrode(s) using known deposition techniques. Theelectrode-exposed surfaces can be inserted within the sensor body,planar with the sensor body, or extending from the sensor body. Althoughsome examples of membrane systems have been provided above, the conceptsdescribed herein can be applied to numerous known architectures notdescribed herein.

Sensor Electronics

In some embodiments, the sensing region may include reference and/orelectrodes associated with the glucose-measuring working electrode andseparate reference and/or counter electrodes associated with theoptional auxiliary working electrode(s). In yet another embodiment, thesensing region may include a glucose-measuring working electrode, anauxiliary working electrode, two counter electrodes (one for eachworking electrode), and one shared reference electrode. In yet anotherembodiment, the sensing region may include a glucose-measuring workingelectrode, an auxiliary working electrode, two reference electrodes, andone shared counter electrode. However, a variety of electrode materialsand configurations can be used with the implantable analyte sensor ofthe preferred embodiments.

In some alternative embodiments, the working electrodes areinterdigitated. In some alternative embodiments, the working electrodeseach comprise multiple exposed electrode surfaces; one advantage ofthese architectures is to distribute the measurements across a greatersurface area to overcome localized problems that may occur in vivo, forexample, with the host's immune response at the biointerface.Preferably, the glucose-measuring and auxiliary working electrodes areprovided within the same local environment, such as described in moredetail elsewhere herein.

FIG. 4 is a block diagram that illustrates the continuous glucose sensorelectronics in one embodiment. In this embodiment, a first potentiostat36 is provided that is operatively associated with the glucose-measuringworking electrode 16. The first potentiostat 36 measures a current valueat the glucose-measuring working electrode and preferably includes aresistor (not shown) that translates the current into voltage. Anoptional second potentiostat 37 is provided that is operativelyassociated with the optional auxiliary working electrode 18. The secondpotentiostat 37 measures a current value at the auxiliary workingelectrode 18 and preferably includes a resistor (not shown) thattranslates the current into voltage. It is noted that in someembodiments, the optional auxiliary electrode can be configured to sharethe first potentiostat with the glucose-measuring working electrode. AnA/D converter 38 digitizes the analog signals from the potentiostats 36,37 into counts for processing. Accordingly, resulting raw data streams(in counts) can be provided that are directly related to the currentmeasured by each of the potentiostats 36 and 37.

A microprocessor 40, also referred to as the processor module, is thecentral control unit that houses EEPROM 42 and SRAM 44, and controls theprocessing of the sensor electronics. It is noted that certainalternative embodiments can utilize a computer system other than amicroprocessor to process data as described herein. In other alternativeembodiments, an application-specific integrated circuit (ASIC) can beused for some or all the sensor's central processing. The EEPROM 42provides semi-permanent storage of data, for example, storing data suchas sensor identifier (ID) and programming to process data streams (forexample, such as described in copending U.S. patent application Ser. No.10/633,367, which is incorporated by reference herein in its entirety.The SRAM 44 can be used for the system's cache memory, for example fortemporarily storing recent sensor data. In some alternative embodiments,memory storage components comparable to EEPROM and SRAM may be usedinstead of or in addition to the preferred hardware, such as dynamicRAM, non-static RAM, rewritable ROMs, flash memory, or the like.

A battery 46 is operably connected to the microprocessor 40 and providesthe necessary power for the sensor 10 a. In one embodiment, the batteryis a Lithium Manganese Dioxide battery, however any appropriately sizedand powered battery can be used (for example, AAA, Nickel-cadmium,Zinc-carbon, Alkaline, Lithium, Nickel-metal hydride, Lithium-ion,Zinc-air, Zinc-mercury oxide, Silver-zinc, and/or hermetically-sealed).In some embodiments the battery is rechargeable. In some embodiments, aplurality of batteries can be used to power the system. In someembodiments, one or more capacitors can be used to power the system. AQuartz Crystal 48 may be operably connected to the microprocessor 40 tomaintain system time for the computer system as a whole.

An RF Transceiver 50 may be operably connected to the microprocessor 40to transmit the sensor data from the sensor 10 to a receiver (see FIGS.4 and 5) within a wireless transmission 52 via antenna 54. Although anRF transceiver is shown here, some other embodiments can include a wiredrather than wireless connection to the receiver. In yet otherembodiments, the receiver can be transcutaneously powered via aninductive coupling, for example. A second quartz crystal 56 can providethe system time for synchronizing the data transmissions from the RFtransceiver. It is noted that the transceiver 50 can be substituted witha transmitter in other embodiments. In some alternative embodimentsother mechanisms such as optical, infrared radiation (IR), ultrasonic,or the like may be used to transmit and/or receive data.

Receiver

FIG. 5 is a schematic drawing of a receiver for the continuous glucosesensor in one embodiment. The receiver 58 comprises systems necessary toreceive, process, and display sensor data from the analyte sensor, suchas described in more detail elsewhere herein. Particularly, the receiver58 may be a pager-sized device, for example, and house a user interfacethat has a plurality of buttons and/or keypad and a liquid crystaldisplay (LCD) screen, and which may include a backlight. In someembodiments the user interface may also include a speaker, and avibrator such as described with reference to FIG. 6.

FIG. 6 is a block diagram of the receiver electronics in one embodiment.In some embodiments, the receiver comprises a configuration such asdescribed with reference to FIG. 5, above. However, the receiver maycomprise any reasonable configuration, including a desktop computer,laptop computer, a personal digital assistant (PDA), a server (local orremote to the receiver), or the like. In some embodiments, a receivermay be adapted to connect (via wired or wireless connection) to adesktop computer, laptop computer, a PDA, a server (local or remote tothe receiver), or the like in order to download data from the receiver.In some alternative embodiments, the receiver may be housed within ordirectly connected to the sensor in a manner that allows sensor andreceiver electronics to work directly together and/or share dataprocessing resources. Accordingly, the receiver, including itselectronics, may be generally described as a “computer system.”

A quartz crystal 60 may be operably connected to an RF transceiver 62that together function to receive and synchronize data streams via anantenna 64 (for example, transmission 52 from the RF transceiver 50shown in FIG. 4). Once received, a microprocessor 66 can process thesignals, such as described below.

The microprocessor 66, also referred to as the processor module, is thecentral control unit that provides the processing, such as storing data,calibrating sensor data, downloading data, controlling the userinterface by providing prompts, messages, warnings and alarms, or thelike. The EEPROM 68 may be operably connected to the microprocessor 66and provides semi-permanent storage of data, storing data such asreceiver ID and programming to process data streams (for example,programming for performing calibration and other algorithms describedelsewhere herein). SRAM 70 may be used for the system's cache memory andis helpful in data processing. For example, the SRAM stores informationfrom the continuous glucose sensor for later recall by the patient or adoctor; a patient or doctor can transcribe the stored information at alater time to determine compliance with the medical regimen or acomparison of glucose concentration to medication administration (forexample, this can be accomplished by downloading the information throughthe pc com port 76). In addition, the SRAM 70 can also store updatedprogram instructions and/or patient specific information. In somealternative embodiments, memory storage components comparable to EEPROMand SRAM can be used instead of or in addition to the preferredhardware, such as dynamic RAM, non-static RAM, rewritable ROMs, flashmemory, or the like.

A battery 72 may be operably connected to the microprocessor 66 andprovides power for the receiver. In one embodiment, the battery is astandard AAA alkaline battery, however any appropriately sized andpowered battery can be used. In some embodiments, a plurality ofbatteries can be used to power the system. In some embodiments, a powerport (not shown) is provided permit recharging of rechargeablebatteries. A quartz crystal 84 may be operably connected to themicroprocessor 66 and maintains system time for the system as a whole.

A PC communication (com) port 76 can be provided to enable communicationwith systems, for example, a serial communications port, allows forcommunicating with another computer system (for example, PC, PDA,server, or the like). In one exemplary embodiment, the receiver is ableto download historical data to a physician's PC for retrospectiveanalysis by the physician. The PC communication port 76 can also be usedto interface with other medical devices, for example pacemakers,implanted analyte sensor patches, infusion devices, telemetry devices,or the like.

A user interface 78 comprises a keypad 80, speaker 82, vibrator 84,backlight 86, liquid crystal display (LCD) 88, and one or more buttons90. The components that comprise the user interface 78 provide controlsto interact with the user. The keypad 80 can allow, for example, inputof user information about himself/herself, such as mealtime, exercise,insulin administration, and reference glucose values. The speaker 82 canprovide, for example, audible signals or alerts for conditions such aspresent and/or predicted hyper- and hypoglycemic conditions. Thevibrator 84 can provide, for example, tactile signals or alerts forreasons such as described with reference to the speaker, above. Thebacklight 94 can be provided, for example, to aid the user in readingthe LCD in low light conditions. The LCD 88 can be provided, forexample, to provide the user with visual data output. In someembodiments, the LCD is a touch-activated screen. The buttons 90 canprovide for toggle, menu selection, option selection, mode selection,and reset, for example. In some alternative embodiments, a microphonecan be provided to allow for voice-activated control.

The user interface 78, which is operably connected to the microprocessor70 serves to provide data input and output for the continuous analytesensor. In some embodiments, prompts can be displayed to inform the userabout necessary maintenance procedures, such as “Calibrate Sensor” or“Replace Battery.” In some embodiments, prompts or messages can bedisplayed on the user interface to convey information to the user, suchas malfunction, outlier values, missed data transmissions, or the like.Additionally, prompts can be displayed to guide the user throughcalibration of the continuous glucose sensor, for example when to obtaina reference glucose value.

Keypad, buttons, touch-screen, and microphone are all examples ofmechanisms by which a user can input data directly into the receiver. Aserver, personal computer, personal digital assistant, insulin pump, andinsulin pen are examples of external devices that can be connected tothe receiver via PC com port 76 to provide useful information to thereceiver. Other devices internal or external to the sensor that measureother aspects of a patient's body (for example, temperature sensor,accelerometer, heart rate monitor, oxygen monitor, or the like) can beused to provide input helpful in data processing. In one embodiment, theuser interface can prompt the patient to select an activity most closelyrelated to their present activity, which can be helpful in linking to anindividual's physiological patterns, or other data processing. Inanother embodiment, a temperature sensor and/or heart rate monitor canprovide information helpful in linking activity, metabolism, and glucoseexcursions of an individual. While a few examples of data input havebeen provided here, a variety of information can be input and can behelpful in data processing as will be understood by one skilled in theart.

Calibration Systems and Methods

As described above in the Overview Section, continuous analyte sensorsdefine a relationship between sensor-generated measurements and areference measurement that is meaningful to a user (for example, bloodglucose in mg/dL). This defined relationship must be monitored to ensurethat the continuous analyte sensor maintains a substantially accuratecalibration and thereby continually provides meaningful values to auser. Unfortunately, both sensitivity m and baseline b of thecalibration are subject to changes that occur in vivo over time (forexample, hours to months), requiring updates to the calibration.Generally, any physical property that influences diffusion or transportof molecules through the membrane can alter the sensitivity (and/orbaseline) of the calibration. Physical properties that can alter thetransport of molecules include, but are not limited to, blockage ofsurface area due to foreign body giant cells and other barrier cells atthe biointerface, distance of capillaries from the membrane, foreignbody response/capsule, disease, tissue ingrowth, thickness of membranesystem, or the like.

In one example of a change in transport of molecules, an implantableglucose sensor is implanted in the subcutaneous space of a human, whichis at least partially covered with a biointerface membrane, such asdescribed in co-pending U.S. patent application Ser. No. 10/647,065,which is incorporated by reference herein in its entirety. Although thebody's natural response to a foreign object is to encapsulate thesensor, the architecture of this biointerface membrane encourages tissueingrowth and neo-vascularization over time, providing transport ofsolutes (for example, glucose and oxygen) close to the membrane thatcovers the electrodes. While not wishing to be bound by theory, it isbelieved that ingrowth of vascularized tissue matures (changes) overtime, beginning with a short period of high solute transport during thefirst few days after implantation, continuing through a time period ofsignificant tissue ingrowth a few days to a week or more afterimplantation during which low solute transport to the membrane has beenobserved, and into a mature state of vascularized tissue during whichthe bed of vascularized tissue provides moderate to high solutetransport, which can last for months and even longer after implantation.In some embodiments, this maturation process accounts for a substantialportion of the change in sensitivity and/or baseline of the calibrationover time due to changes in solute transport to the membrane.

Accordingly, in one aspect of the preferred embodiments, systems andmethods are provided for measuring changes in sensitivity, also referredto as changes in solute transport or biointerface changes, of an analytesensor 10 implanted in a host over a time period. Preferably, thesensitivity measurement is a signal obtained by measuring a constantanalyte other than the analyte being measured by the analyte sensor. Forexample, in a glucose sensor, a non-glucose constant analyte ismeasured, wherein the signal is measured beneath the membrane system 22on the glucose sensor 10. While not wishing to be bound by theory, it isbelieved that by monitoring the sensitivity over a time period, a changeassociated with solute transport through the membrane system 22 can bemeasured and used as an indication of a sensitivity change in theanalyte measurement. In other words, a biointerface monitor is provided,which is capable of monitoring changes in the biointerface surroundingan implantable device, thereby enabling the measurement of sensitivitychanges of an analyte sensor over time.

In some embodiments, the analyte sensor 10 is provided with an auxiliaryelectrode 18 configured as a transport-measuring electrode disposedbeneath the membrane system 22. The transport-measuring electrode can beconfigured to measure any of a number of substantially constant analytesor factors, such that a change measured by the transport-measuringelectrode can be used to indicate a change in solute (for example,glucose) transport to the membrane system 22. Some examples ofsubstantially constant analytes or factors that can be measured include,but are not limited to, oxygen, carboxylic acids (such as urea), aminoacids, hydrogen, pH, chloride, baseline, or the like. Thus, thetransport-measuring electrode provides an independent measure of changesin solute transport to the membrane, and thus sensitivity changes overtime.

In some embodiments, the transport-measuring electrode measures analytessimilar to the analyte being measured by the analyte sensor. Forexample, in some embodiments of a glucose sensor, water soluble analytesare believed to better represent the changes in sensitivity to glucoseover time than non-water soluble analytes (due to the water-solubilityof glucose), however relevant information may be ascertained from avariety of molecules. Although some specific examples are describedherein, one skilled in the art appreciates a variety of implementationsof sensitivity measurements that can be used as to qualify or quantifysolute transport through the biointerface of the analyte sensor.

In one embodiment of a glucose sensor, the transport-measuring electrodeis configured to measure urea, which is a water-soluble constant analytethat is known to react directly or indirectly at a hydrogen peroxidesensing electrode (similar to the working electrode of the glucosesensor example described in more detail above). In one exemplaryimplementation wherein urea is directly measured by thetransport-measuring electrode, the glucose sensor comprises a membranesystem as described in more detail above, however, does not include anactive interference domain or active enzyme directly above thetransport-measuring electrode, thereby allowing the urea to pass throughthe membrane system to the electroactive surface for measurementthereon. In one alternative exemplary implementation wherein urea isindirectly measured by the transport-measuring electrode, the glucosesensor comprises a membrane system as described in more detail above,and further includes an active uricase oxidase domain located directlyabove the transport-measuring electrode, thereby allowing the urea toreact at the enzyme and produce hydrogen peroxide, which can be measuredat the electroactive surface thereon.

In some embodiments, the change in sensitivity is measured by measuringa change in oxygen concentration, which can be used to provide anindependent measurement of the maturation of the biointerface, and toindicate when recalibration of the system may be advantageous. In onealternative embodiment, oxygen is measured using pulsed amperometricdetection on the glucose-measuring working electrode 16 (eliminating theneed for a separate auxiliary electrode). In another embodiment, theauxiliary electrode is configured as an oxygen-measuring electrode. Inanother embodiment, an oxygen sensor (not shown) is added to the glucosesensor, as is appreciated by one skilled in the art, eliminating theneed for an auxiliary electrode.

In some embodiments, a stability module is provided, wherein thesensitivity measurement changes can be quantified such that a co-analyteconcentration threshold is determined. A co-analyte threshold isgenerally defined as a minimum amount of co-analyte required to fullyreact with the analyte in an enzyme-based analyte sensor in anon-limiting manner. The minimum co-analyte threshold is preferablyexpressed as a ratio (for example, a glucose-to-oxygen ratio) thatdefines a concentration of co-analyte required based on a concentrationof analyte available to ensure that the enzyme reaction is limited onlyby the analyte. While not wishing to be bound by theory, it is believedthat by determining a stability of the analyte sensor based on aco-analyte threshold, the processor module can be configured tocompensate for instabilities in the glucose sensor accordingly, forexample by filtering the unstable data, suspending calibration ordisplay, or the like.

In one such embodiment, a data stream from an analyte signal ismonitored and a co-analyte threshold set, whereby the co-analytethreshold is determined based on a signal-to-noise ratio exceeding apredetermined threshold. In one embodiment, the signal-to-noisethreshold is based on measurements of variability and the sensor signalover a time period, however one skilled in the art appreciates thevariety of systems and methods available for measuring signal-to-noiseratios. Accordingly, the stability module can be configured to setdetermine the stability of the analyte sensor based on the co-analytethreshold, or the like.

In some embodiments, the stability module is configured to prohibitcalibration of the sensor responsive to the stability (or instability)of the sensor. In some embodiments, the stability module can beconfigured to trigger filtering of the glucose signal responsive to astability (or instability) of the sensor.

In some embodiments, sensitivity changes can be used to trigger arequest for one or more new reference glucose values from the host,which can be used to recalibrate the sensor. In some embodiments, thesensor is re-calibrated responsive to a sensitivity change exceeding apreselected threshold value. In some embodiments, the sensor iscalibrated repeatedly at a frequency responsive to the measuredsensitivity change. Using these techniques, patient inconvenience can beminimized because reference glucose values are generally only requestedwhen timely and appropriate (namely, when a sensitivity or baselineshift is diagnosed).

In some alternative embodiments, sensitivity changes can be used toupdate calibration. For example, the measured change in transport can beused to update the sensitivity m in the calibration equation. While notwishing to be bound by theory, it is believed that in some embodiments,the sensitivity m of the calibration of the glucose sensor issubstantially proportional to the change in solute transport measured bythe transport-measuring electrode.

It should be appreciated by one skilled in the art that in someembodiments, the implementation of sensitivity measurements of thepreferred embodiments typically necessitate an addition to, ormodification of, the existing electronics (for example, potentiostatconfiguration or settings) of the glucose sensor and/or receiver.

In some embodiments, the signal from the oxygen measuring electrode maybe digitally low-pass filtered (for example, with a passband of 0-10⁻⁵Hz, dc-24 hour cycle lengths) to remove transient fluctuations inoxygen, due to local ischemia, postural effects, periods of apnea, orthe like. Since oxygen delivery to tissues is held in tight homeostaticcontrol, this filtered oxygen signal should oscillate about a relativelyconstant. In the interstitial fluid, it is thought that the levels areabout equivalent with venous blood (40 mmHg). Once implanted, changes inthe mean of the oxygen signal (for example, >5%) may be indicative ofchange in transport through the biointerface (change in sensorsensitivity and/or baseline due to changes in solute transport) and theneed for system recalibration.

The oxygen signal may also be used in its unfiltered or a minimallyfiltered form to detect or predict oxygen deprivation-induced artifactin the glucose signal, and to control display of data to the user, orthe method of smoothing, digital filtering, or otherwise replacement ofglucose signal artifact. In some embodiments, the oxygen sensor may beimplemented in conjunction with any signal artifact detection orprediction that may be performed on the counter electrode or workingelectrode voltage signals of the electrode system. Co-pending U.S.patent application Ser. No. 10/648,849, which is incorporated byreference in its entirety herein, describes some methods of signalartifact detection and replacement that may be useful such as describedherein.

Preferably, the transport-measuring electrode is located within the samelocal environment as the electrode system associated with themeasurement of glucose, such that the transport properties at thetransport-measuring electrode are substantially similar to the transportproperties at the glucose-measuring electrode.

In a second aspect the preferred embodiments, systems and methods areprovided for measuring changes baseline, namely non-glucose relatedelectroactive compounds in the host. Preferably the auxiliary workingelectrode is configured to measure the baseline of the analyte sensorover time. In some embodiments, the glucose-measuring working electrode16 is a hydrogen peroxide sensor coupled to a membrane system 22containing an active enzyme 32 located above the electrode (such asdescribed in more detail with reference to FIGS. 1 to 4, above). In someembodiments, the auxiliary working electrode 18 is another hydrogenperoxide sensor that is configured similar to the glucose-measuringworking electrode however a portion 34 of the membrane system 22 abovethe base-measuring electrode does not have active enzyme therein, suchas described in more detail with reference to FIGS. 3A and 3B. Theauxiliary working electrode 18 provides a signal substantiallycomprising the baseline signal, b, which can be (for example,electronically or digitally) subtracted from the glucose signal obtainedfrom the glucose-measuring working electrode to obtain the signalcontribution due to glucose only according to the following equation:

Signal_(glucose only)=Signal_(glucose-measuring working electrode)−Signal_(baseline-measuring working electrode)

In some embodiments, electronic subtraction of the baseline signal fromthe glucose signal can be performed in the hardware of the sensor, forexample using a differential amplifier. In some alternative embodiments,digital subtraction of the baseline signal from the glucose signal canbe performed in the software or hardware of the sensor or an associatedreceiver, for example in the microprocessor.

One aspect the preferred embodiments provides for a simplifiedcalibration technique, wherein the variability of the baseline has beeneliminated (namely, subtracted). Namely, calibration of the resultantdifferential signal (Signal_(glucose only)) can be performed with asingle matched data pair by solving the following equation:

y=mx

While not wishing to be bound by theory, it is believed that bycalibrating using this simplified technique, the sensor is made lessdependent on the range of values of the matched data pairs, which can besensitive to human error in manual blood glucose measurements, forexample. Additionally, by subtracting the baseline at the sensor (ratherthan solving for the baseline b as in conventional calibration schemes),accuracy of the sensor may increase by altering control of this variable(baseline b) from the user to the sensor. It is additionally believedthat variability introduced by sensor calibration may be reduced.

In some embodiments, the glucose-measuring working electrode 16 is ahydrogen peroxide sensor coupled to a membrane system 22 containing anactive enzyme 32 located above the electrode, such as described in moredetail above; however the baseline signal is not subtracted from theglucose signal for calibration of the sensor. Rather, multiple matcheddata pairs are obtained in order to calibrate the sensor (for exampleusing y=mx+b) in a conventional manner, and the auxiliary workingelectrode 18 is used as an indicator of baseline shifts in the sensorsignal. Namely, the auxiliary working electrode 18 is monitored forchanges above a certain threshold. When a significant change isdetected, the system can trigger a request (for example, from thepatient or caregiver) for a new reference glucose value (for example,SMBG), which can be used to recalibrate the sensor. By using theauxiliary working electrode signal as an indicator of baseline shifts,recalibration requiring user interaction (namely, new reference glucosevalues) can be minimized due to timeliness and appropriateness of therequests. In some embodiments, the sensor is re-calibrated responsive toa baseline shifts exceeding a preselected threshold value. In someembodiments, the sensor is calibrated repeatedly at a frequencyresponsive to the rate-of-change of the baseline.

In yet another alternative embodiment, the electrode system of thepreferred embodiments is employed as described above, includingdetermining the differential signal of glucose less baseline current inorder to calibrate using the simplified equation (y=mx), and theauxiliary working electrode 18 is further utilized as an indicator ofbaseline shifts in the sensor signal. While not wishing to be bound bytheory, it is believed that shifts in baseline may also correlate and/orbe related to changes in the sensitivity m of the glucose signal.Consequently, a shift in baseline may be indicative of a change insensitivity m. Therefore, the auxiliary working electrode 18 ismonitored for changes above a certain threshold. When a significantchange is detected, the system can trigger a request (for example, fromthe patient or caregiver) for a new reference glucose value (forexample, SMBG), which can be used to recalibrate the sensor. By usingthe auxiliary signal as an indicator of possible sensitivity changes,recalibration requiring user interaction (new reference glucose values)can be minimized due to timeliness and appropriateness of the requests.

It is noted that infrequent new matching data pairs may be useful overtime to recalibrate the sensor because the sensitivity m of the sensormay change over time (for example, due to maturation of the biointerfacethat may increase or decrease the glucose and/or oxygen availability tothe sensor). However, the baseline shifts that have conventionallyrequired numerous and/or regular blood glucose reference measurementsfor updating calibration (for example, due to interfering species,metabolism changes, or the like) can be consistently and accuratelyeliminated using the systems and methods of the preferred embodiments,allowing reduced interaction from the patient (for example, requestingless frequent reference glucose values such as daily or even asinfrequently as monthly).

An additional advantage of the sensor of the preferred embodimentsincludes providing a method of eliminating signal effects of interferingspecies, which have conventionally been problematic in electrochemicalglucose sensors. Namely, electrochemical sensors are subject toelectrochemical reaction not only with the hydrogen peroxide (or otheranalyte to be measured), but additionally may react with otherelectroactive species that are not intentionally being measured (forexample, interfering species), which cause an increase in signalstrength due to this interference. In other words, interfering speciesare compounds with an oxidation potential that overlap with the analytebeing measured. Interfering species such as acetaminophen, ascorbate,and urate, are notorious in the art of glucose sensors for producinginaccurate signal strength when they are not properly controlled. Someglucose sensors utilize a membrane system that blocks at least someinterfering species, such as ascorbate and urate. Unfortunately, it isdifficult to find membranes that are satisfactory or reliable in use,especially in vivo, which effectively block all interferants and/orinterfering species. The prior art is crowded with literature dedicatedto efforts toward reducing or eliminating interfering species (forexample, see U.S. Pat. No. 4,776,944, U.S. Pat. No. 5,356,786, U.S. Pat.No. 5,593,852, U.S. Pat. No. 5,776,324B1, and U.S. Pat. No. 6,356,776).

The preferred embodiments are particularly advantageous in theirinherent ability to eliminate the erroneous transient and non-transientsignal effects normally caused by interfering species. For example, ifan interferant such as acetaminophen is ingested by a host implantedwith a conventional implantable electrochemical glucose sensor (namely,one without means for eliminating acetaminophen), a transientnon-glucose related increase in signal output would occur. However, byutilizing the electrode system of the preferred embodiments, bothworking electrodes respond with substantially equivalent increasedcurrent generation due to oxidation of the acetaminophen, which would beeliminated by subtraction of the auxiliary electrode signal from theglucose-measuring electrode signal.

In summary, the system and methods of the preferred embodiments simplifythe computation processes of calibration, decreases the susceptibilityintroduced by user error in calibration, and eliminates the effects ofinterfering species. Accordingly, the sensor requires less interactionby the patient (for example, less frequent calibration), increasespatient convenience (for example, few reference glucose values), andimproves accuracy (via simple and reliable calibration).

In another aspect of the preferred embodiments, the analyte sensor isconfigured to measure any combination of changes in baseline and/or insensitivity, simultaneously and/or iteratively, using any of theabove-described systems and methods. While not wishing to be bound bytheory, the preferred embodiments provide for improved calibration ofthe sensor, increased patient convenience through less frequent patientinteraction with the sensor, less dependence on the values/range of thepaired measurements, less sensitivity to error normally found in manualreference glucose measurements, adaptation to the maturation of thebiointerface over time, elimination of erroneous signal due tointerfering species, and/or self-diagnosis of the calibration for moreintelligent recalibration of the sensor.

Methods and devices that are suitable for use in conjunction withaspects of the preferred embodiments are disclosed in co-pending U.S.patent application Ser. No. 10/885,476 filed Jul. 6, 2004 and entitled“SYSTEMS AND METHODS FOR MANUFACTURE OF AN ANALYTE SENSOR INCLUDING AMEMBRANE SYSTEM”; U.S. patent application Ser. No. 10/842,716, filed May10, 2004 and entitled, “MEMBRANE SYSTEMS INCORPORATING BIOACTIVEAGENTS”; co-pending U.S. patent application Ser. No. 10/838,912 filedMay 3, 2004 and entitled, “IMPLANTABLE ANALYTE SENSOR”; U.S. patentapplication Ser. No. 10/789,359 filed Feb. 26, 2004 and entitled,“INTEGRATED DELIVERY DEVICE FOR A CONTINUOUS GLUCOSE SENSOR”; U.S.application Ser. No. 10/685,636 filed Oct. 28, 2003 and entitled,“SILICONE COMPOSITION FOR MEMBRANE SYSTEM”; U.S. application Ser. No.10/648,849 filed Aug. 22, 2003 and entitled, “SYSTEMS AND METHODS FORREPLACING SIGNAL ARTIFACTS IN A GLUCOSE SENSOR DATA STREAM”; U.S.application Ser. No. 10/646,333 filed Aug. 22, 2003 entitled, “OPTIMIZEDSENSOR GEOMETRY FOR AN IMPLANTABLE GLUCOSE SENSOR”; U.S. applicationSer. No. 10/647,065 filed Aug. 22, 2003 entitled, “POROUS MEMBRANES FORUSE WITH IMPLANTABLE DEVICES”; U.S. application Ser. No. 10/633,367filed Aug. 1, 2003 entitled, “SYSTEM AND METHODS FOR PROCESSING ANALYTESENSOR DATA”; U.S. Pat. No. 6,702,857 entitled “MEMBRANE FOR USE WITHIMPLANTABLE DEVICES”; U.S. application Ser. No. 09/916,711 filed Jul.27, 2001 and entitled “SENSOR HEAD FOR USE WITH IMPLANTABLE DEVICE”;U.S. application Ser. No. 09/447,227 filed Nov. 22, 1999 and entitled“DEVICE AND METHOD FOR DETERMINING ANALYTE LEVELS”; U.S. applicationSer. No. 10/153,356 filed May 22, 2002 and entitled “TECHNIQUES TOIMPROVE POLYURETHANE MEMBRANES FOR IMPLANTABLE GLUCOSE SENSORS”; U.S.application Ser. No. 09/489,588 filed Jan. 21, 2000 and entitled “DEVICEAND METHOD FOR DETERMINING ANALYTE LEVELS”; U.S. application Ser. No.09/636,369 filed Aug. 11, 2000 and entitled “SYSTEMS AND METHODS FORREMOTE MONITORING AND MODULATION OF MEDICAL DEVICES”; and U.S.application Ser. No. 09/916,858 filed Jul. 27, 2001 and entitled “DEVICEAND METHOD FOR DETERMINING ANALYTE LEVELS,” as well as issued patentsincluding U.S. Pat. No. 6,001,067 issued Dec. 14, 1999 and entitled“DEVICE AND METHOD FOR DETERMINING ANALYTE LEVELS”; U.S. Pat. No.4,994,167 issued Feb. 19, 1991 and entitled “BIOLOGICAL FLUID MEASURINGDEVICE”; and U.S. Pat. No. 4,757,022 filed Jul. 12, 1988 and entitled“BIOLOGICAL FLUID MEASURING DEVICE”; U.S. Appl. No. 60/489,615 filedJul. 23, 2003 and entitled “ROLLED ELECTRODE ARRAY AND ITS METHOD FORMANUFACTURE”; U.S. Appl. No. 60/490,010 filed Jul. 25, 2003 and entitled“INCREASING BIAS FOR OXYGEN PRODUCTION IN AN ELECTRODE ASSEMBLY”; U.S.Appl. No. 60/490,009 filed Jul. 25, 2003 and entitled “OXYGEN ENHANCINGENZYME MEMBRANE FOR ELECTROCHEMICAL SENSORS”; U.S. application Ser. No.10/896,312 filed Jul. 21, 2004 and entitled “OXYGEN-GENERATING ELECTRODEFOR USE IN ELECTROCHEMICAL SENSORS”; U.S. application Ser. No.10/896,637 filed Jul. 21, 2004 and entitled “ROLLED ELECTRODE ARRAY ANDITS METHOD FOR MANUFACTURE”; U.S. application Ser. No. 10/896,772 filedJul. 21, 2004 and entitled “INCREASING BIAS FOR OXYGEN PRODUCTION IN ANELECTRODE ASSEMBLY”; U.S. application Ser. No. 10/896,639 filed Jul. 21,2004 and entitled “OXYGEN ENHANCING ENZYME MEMBRANE FOR ELECTROCHEMICALSENSORS”; U.S. application Ser. No. 10/897,377 filed Jul. 21, 2004 andentitled “ELECTROCHEMICAL SENSORS INCLUDING ELECTRODE SYSTEMS WITHINCREASED OXYGEN GENERATION”. The foregoing patent applications andpatents are incorporated herein by reference in their entireties.

All references cited herein are incorporated herein by reference intheir entireties. To the extent publications and patents or patentapplications incorporated by reference contradict the disclosurecontained in the specification, the specification is intended tosupersede and/or take precedence over any such contradictory material.

The term “comprising” as used herein is synonymous with “including,”“containing,” or “characterized by,” and is inclusive or open-ended anddoes not exclude additional, unrecited elements or method steps.

All numbers expressing quantities of ingredients, reaction conditions,and so forth used in the specification and claims are to be understoodas being modified in all instances by the term “about.” Accordingly,unless indicated to the contrary, the numerical parameters set forth inthe specification and attached claims are approximations that can varydepending upon the desired properties sought to be obtained by thepresent invention. At the very least, and not as an attempt to limit theapplication of the doctrine of equivalents to the scope of the claims,each numerical parameter should be construed in light of the number ofsignificant digits and ordinary rounding approaches.

The above description discloses several methods and materials of thepresent invention. This invention is susceptible to modifications in themethods and materials, as well as alterations in the fabrication methodsand equipment. Such modifications will become apparent to those skilledin the art from a consideration of this disclosure or practice of theinvention disclosed herein. Consequently, it is not intended that thisinvention be limited to the specific embodiments disclosed herein, butthat it cover all modifications and alternatives coming within the truescope and spirit of the invention as embodied in the attached claims.

1. A system for measuring glucose in a host, the system comprising: afirst working electrode configured to generate a first signal associatedwith a glucose concentration in a host; an auxiliary electrodeconfigured to generate an auxiliary signal associated with an auxiliaryanalyte concentration in the host; and a processor module configured tocalibrate the first signal based at least in part on the auxiliarysignal.
 2. The system of claim 1, further comprising a second workingelectrode configured to generate a second signal, wherein the secondsignal is associated with a non-glucose related electroactive compound,wherein the second working electrode is disposed beneath a non-enzymaticportion of a membrane system on a glucose sensor, wherein the firstsignal is associated with a glucose related electroactive compound andthe non-glucose related electroactive compound, and wherein the firstelectrode is disposed beneath an active enzymatic portion of themembrane system on the glucose sensor.
 3. The system of claim 2, furthercomprising a subtraction module configured to subtract the second signalfrom the first signal, whereby a differential signal comprising at leastone glucose sensor data point is determined.
 4. The system of claim 1,wherein the auxiliary electrode is configured to measure at least oneanalyte selected from the group consisting of oxygen, a carboxylic acid,an amino acid, hydrogen, pH, chloride, and combinations thereof.
 5. Thesystem of claim 1, wherein the processor module is configured tocalibrate the first signal in response to a predetermined change in theauxiliary signal.
 6. The system of claim 1, wherein the processor moduleis configured to calibrate the first signal based at least in part on anamplitude of the auxiliary signal.
 7. The system of claim 1, wherein theprocessor module is configured to calibrate the first electrode at apreselected frequency.
 8. The system of claim 7, wherein the preselectedfrequency is based at least in part on a change in the auxiliary signal.9. The system of claim 1, wherein the first working electrode and theauxiliary electrode are configured to be located at a same localenvironment when implanted in a host.
 10. The system of claim 9, whereinthe first electrode and the auxiliary electrode are juxtapositioned withor around each other or are twisted with or around each other.
 11. Thesystem of claim 1, wherein the first working electrode is configured tocontinuously measure the first signal.
 12. The system of claim 11,wherein the first working electrode is configured to intermittentlymeasure the first signal.
 13. The system of claim 1, wherein the sensorcomprises at least one wire.
 14. The system of claim 13, wherein thesensor comprises at least two wires juxtapositioned with or around eachother or twisted with or around each other.
 15. The system of claim 13,wherein the wire has a width of less than about 0.010 inches.